There has been recent interest in the use of mild hypothermia (30-35 degrees C) in the treatment of cerebral ischemia and stroke. The purpose of this project is to define optimal parameters in which hypothermia can be applied in animal models of focal cerebral ischemia. Using an intraluminal suture occlusion model of stroke in the rat, a series of experiments will be performed to determine the optimal depth and duration of hypothermia which provides maximal reduction in infarct size as well as avoiding systemic complications. Additional questions that will be addressed will include the extent to which hypothermia can be delayed and still offer protection as well as whether the protective effects are permanent. This project will then investigate the use of diffusion- weighted MRI (DWI) in characterizing ischemic stroke in response to alterations in temperature. Since it is known that diffusion is affected by temperature changes, experiments relating the apparent diffusion coefficient and various temperatures will be performed. After establishing this relationship in normal animals, experiments will be conducted to characterize the diffusion changes seen with hypothermia and focal ischemia. The time course of diffusion changes and infarct size will be studied as well as the potential of DWI as a predictor of infarct severity. To examine the feasibility of hypothermia in a potential clinical setting, hypothermia will be used in conjunction with a thrombolytic agent in a rabbit model of thromboembolic stroke. The time course of ischemia and response to treatment with hypothermia and thrombolysis will be monitored using sequential diffusion and perfusion MRIs. The final years of this grant will focus on mechanisms that may explain the protective effect of hypothermia. Cerebral blood flow may be an important factor in its protective effect and will be studied using perfusion MRI techniques as well as established laboratory methods. Other parameters such as blood brain barrier integrity, edema and inflammatory cell infiltration will be measured at various temperatures. The knowledge gained from this project will have direct implications in the treatment of ischemic stroke in humans as well as the prophylactic use of hypothermia in both medical and surgical patients.